New twist in tale of BSE's beginnings

THE discovery that a rare brain disease in cows can mutate into BSE has given new life to the theory that mad cow disease started out in cattle, rather than crossing over from sheep.

When BSE emerged in British cattle in the mid-1980s, the leading theory was that they had initially contracted the disease by eating feed containing the remains of sheep infected with scrapie. Both BSE and scrapie are caused by infectious prions, misshapen forms of a normal brain protein. Having made this species jump, BSE would have spread as cattle carcasses were processed into animal fodder and fed back to cows.

Yet attempts to duplicate BSE by deliberately giving scrapie to cows have failed, and many countries included sheep remains in cattle feed without creating BSE. This has led some scientists to speculate that BSE arose as a rare spontaneous condition in cattle, which spread to other cows when they ate these animals' remains.

The new twist to the story comes from studies of a disease called bovine amyloidotic spongiform encephalopathy, or BASE. It was discovered in 2003, when two Italian cows, out of tens of thousands of European cattle screened for BSE at slaughter, were found to have a prion disease that seemed different from BSE. The BASE prion had a lower molecular weight and one, rather than two, sugars bound to it. The brains of cows with BASE were also damaged in different places from those with BSE, and had dense protein deposits called amyloid that are not seen in BSE. Similar prions have also turned up in France, Germany and Japan.

Fabrizio Tagliavini and his colleagues at the Carlo Besta Neurological Institute in Milan, Italy, have now injected material from the brains of cows with BSE or BASE into mice. In animals genetically altered to make cow PrP - the normal form of the prion protein - BSE and BASE produced different symptoms and brain damage, confirming that BASE is a different disease.

When Tagliavini injected material from the brains of cows with BASE into mice with normal mouse PrP, none developed symptoms and only one tested positive for a prion - which looked like BSE, not BASE. When brain material from this first groups of mice was injected into a second round of mice, all of them developed typical BSE (PLoS Pathogens, DOI: 10.1371/journal.ppat.0030031). In unpublished experiments, Tagliavini has shown that the conversion of BASE prion to BSE can also occur in the spleens of mice engineered to carry cow PrP.

If BASE can mutate into BSE, this could well be how mad cow disease emerged. "I think BASE is a natural prion disease of older cattle, which turned into BSE," says Tagliavini.

Another possibility is that BASE turned into BSE after cattle remains were fed to sheep. In preliminary research, Hubert Laude of INRA, the French national agricultural research agency, in Jouy-en-Josas says that he has got BASE to turn into BSE in mice engineered to carry sheep PrP, but not in mice with cow or human PrP.

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